Breast cancer is a great public health concern, but fortunately it is very treatable with high survival rates such that the majority of women are able to remain disease-free for many decades. As a result, a large cohort of women are now reaching late-life who have received previous treatments including chemotherapy, and they are now at an age where the development of memory decline becomes a concern. Hence it is of great interest to learn whether treatment for breast cancer increases the likelihood of cognitive decline in the elder years. This project will build on the "Integrating Aging and Cancer Research" program at the University of Iowa which encourages multidisciplinary collaborations that may lead to new insights into late-life outcomes. This revised application will determine the longitudinal effects of previous chemotherapy on late-life cognitive changes. The Iowa Cancer Registry of the State Health Registry will provide valuable assistance in identifying women who have survived more than 10 years and are now over age 65 and residing in southeast Iowa. In response to the previous reviews this study will now enroll a well-defined sample that will exclude participants who have also received radiation to create a homogenous group. The comprehensive neuropsychological assessment will be combined with state of the art magnetic resonance and diffusion tensor imaging to permit an analysis of regional brain differences in relation to cognitive outcomes. Previous studies have detected cognitive changes following acute treatment, but no studies have focused on the elderly population of long-term survivors. This application responds to Program Announcement (PA) Number: PA-05-142 "Biobehavioral Methods to Improve Outcomes Research" with an objective to foster "development of collaborative studies to expand the understanding of biobehavioral factors that influence disease prevention, improve health outcomes, or increase quality of life." Finally, this appliciation will utilize the strengths of the Free Radial and Radiation Biology Program to translate the clinical evaluation to underlying neural changes. To this end, we will build on emerging evidence that the deleterious effects of chemotherapy may involve the acceleration of degenerative processes such as mitochondrial DNA damage and alterations in oxidative stress that are increasingly associated with neural aging. Therefore this study will also explore the role of mitochondrial deletions as a mechanism that may contribute to brain changes. By exploring the underlying mechanisms for neurodegeneration, specific testable treatments and prevention strategies may ultimately be developed.